Pharmacodynamics and Pharmacokinetics of Irbesartan in Patients With Mild to Moderate Hypertension.

BACKGROUND: The pharmacodynamics (plasma angiotensin II [AII], plasma renin activity [PRA], renal function, blood pressure [BP], urinary excretion of major metabolites of prostacyclin [PGI(2)-M], and thromboxane A(2) [TXA(2)-M]) and pharmacokinetics of irbesartan were assessed in hypertensive patients. METHODS AND RESULTS: Twenty-four white patients with seated diastolic blood pressure 95 to 110 mmHg were randomized to double-blind irbesartan 300 mg or placebo once daily for 4 weeks, following a placebo lead-in. Irbesartan-treated patients had significantly greater 24-hour area under the curve values for mean change from baseline in AII and PRA versus placebo-treated patients on day B15 (AII [pg |mZ h/mL]: 261 +/- 515 vs 12 +/- 51; PRA [(ng/mL/h); h]:74 +/-162 vs -2 +/-14; P values >.05). Irbesartan significantly lowered BP without clinically important changes in renal function. Irbesartan had no effect on 24-hour urinary TXA(2)-M excretion, but significantly increased 24-hour PGI(2)-M excretion versus placebo on day B29 (20.7 +/- 23 pg/mg creatinine vs _2.3 +/- 43 pg/mg creatinine; P <.05). Pharmacokinetics were comparable to those from previous studies. The hourly relationship between plasma irbesartan concentration and antihypertensive effect indicated a broad, clockwise hysteresis, with peak concentration occurring at 1.5 hours, whereas peak antihypertensive effect occurred at 4 hours. CONCLUSIONS: Irbesartan increases plasma AII and PRA and lowers BP consistent with AT(1) receptor blockade, without clinically important effects on renal function.